scholarly journals SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

2017 ◽  
Vol 42 (4) ◽  
pp. 1358-1365 ◽  
Author(s):  
Piyush Sharma ◽  
Vishal Khairnar ◽  
Ivana Vrhovac Madunić ◽  
Yogesh Singh ◽  
Aleksandra Pandyra ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Glucose Uptake ◽  
Bacterial Load ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Hepatic Expression ◽  
Cell Functions ◽  
Tnf Α ◽  
Listeria Infection ◽  
Deficient Mice

Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na+-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose concentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x104 CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1–/– mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.

scholarly journals Partial Protection against Helicobacter pylori in the Absence of Mast Cells in Mice

2009 ◽  
Vol 77 (12) ◽  
pp. 5543-5550 ◽  
Author(s):  
Hua Ding ◽  
John G. Nedrud ◽  
Barry Wershil ◽  
Raymond W. Redline ◽  
Thomas G. Blanchard ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Mast Cell ◽  
Mast Cells ◽  
Bacterial Load ◽  
Interleukin 17 ◽  
Wild Type ◽  
Spleen Cells ◽  
Tnf Α ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT The goal of this study is to evaluate the contribution of mast cells to Helicobacter pylori immunity in a model of vaccine-induced protection. Mast cell-deficient KitlSl /KitlSl-d and control mice were immunized with H. pylori sonicate plus cholera toxin and challenged with H. pylori, and the bacterial loads, inflammatory infiltrates, and cytokine responses were evaluated and compared at 1, 2, and 4 weeks postchallenge. In vitro stimulation assays were performed using bone marrow-derived mast cells, and recall assays were performed with spleen cells of immunized mast cell-deficient and wild-type mice. Bacterial clearance was observed by 2 weeks postchallenge in mast cell-deficient mice. The bacterial load was reduced by 4.0 log CFU in wild-type mice and by 1.5 log CFU in mast cell-deficient mice. Neutrophil numbers in the gastric mucosa of immune KitlSl /KitlSl-d mice were lower than those for immune wild-type mice (P < 0.05). Levels of gastric interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) were also significantly lower in immune KitlSl /KitlSl-d mice than in wild-type mice (P < 0.001). Immunized mast cell-deficient and wild-type mouse spleen cells produced IFN-γ and IL-17 in response to H. pylori antigen stimulation. TNF-α and CXC chemokines were detected in mast cell supernatants after 24 h of stimulation with H. pylori antigen. The results indicate that mast cells are not essential for but do contribute to vaccine-induced immunity and that mast cells contribute to neutrophil recruitment and inflammation in response to H. pylori.

scholarly journals Expression of NADPH Oxidase-Dependent Resistance to Listeriosis in Mice Occurs during the First 6 to 12 Hours of Liver Infection

2002 ◽  
Vol 70 (12) ◽  
pp. 7179-7181 ◽  
Author(s):  
Ronald LaCourse ◽  
Lynn Ryan ◽  
Robert J. North
Keyword(s):  
Listeria Monocytogenes ◽  
Nadph Oxidase ◽  
Bacterial Load ◽  
Wild Type ◽  
Liver Infection

ABSTRACT Wild-type mice inoculated with Listeria monocytogenes intravenously were capable of reducing the bacterial load in their livers by 90% within 6 h. In contrast, mice with deletions of the gene for NADPH oxidase were incapable of expressing this early oxygen-dependent anti-Listeria defense and consequently showed higher levels of liver infection at later times.

scholarly journals Role of Nitric Oxide in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

2009 ◽  
Vol 83 (16) ◽  
pp. 8004-8011 ◽  
Author(s):  
Young-Sun Lee ◽  
Na Li ◽  
Seungjin Shin ◽  
Hee-Sook Jun
Keyword(s):  
Virus Infection ◽  
Encephalomyocarditis Virus ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Diabetes In Mice ◽  
Tnf Α ◽  
Deficient Mice

ABSTRACT The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic β cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in β-cell destruction by producing soluble mediators such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). To investigate the role of NO and inducible NO synthase (iNOS) in the development of diabetes in EMC-D virus-infected mice, we infected iNOS-deficient DBA/2 mice with EMC-D virus (2 × 102 PFU/mouse). Mean blood glucose levels in EMC-D virus-infected iNOS-deficient mice and wild-type mice were 205.5 and 466.7 mg/dl, respectively. Insulitis and macrophage infiltration were reduced in islets of iNOS-deficient mice compared with wild-type mice at 3 days after EMC-D virus infection. Apoptosis of β cells was decreased in iNOS-deficient mice, as evidenced by reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. There were no differences in mRNA expression of antiapoptotic molecules Bcl-2, Bcl-xL, Bcl-w, Mcl-1, cIAP-1, and cIAP-2 between wild-type and iNOS-deficient mice, whereas expression of proapoptotic Bax and Bak mRNAs was significantly decreased in iNOS-deficient mice. Expression of IL-1β and TNF-α mRNAs was significantly decreased in both islets and macrophages of iNOS-deficient mice compared with wild-type mice after EMC-D virus infection. Nuclear factor κB was less activated in macrophages of iNOS-deficient mice after virus infection. We conclude that NO plays an important role in the activation of macrophages and apoptosis of pancreatic β cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and β-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.

scholarly journals Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment

2010 ◽  
Vol 207 (10) ◽  
pp. 2065-2072 ◽  
Author(s):  
Nathalie T. Joncker ◽  
Nataliya Shifrin ◽  
Frédéric Delebecque ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Wild Type ◽  
Mhc I ◽  
Cell Functions ◽  
Histocompatibility Complex ◽  
Activating Receptors ◽  
Nk Cell Differentiation ◽  
Deficient Mice

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.

scholarly journals TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Rodolfo Soria-Castro ◽  
Ángel R. Alfaro-Doblado ◽  
Gloria Rodríguez-López ◽  
Marcia Campillo-Navarro ◽  
Yatsiri G. Meneses-Preza ◽  
...  
Keyword(s):  
Mast Cell ◽  
Listeria Monocytogenes ◽  
Cytokine Production ◽  
Bacterial Load ◽  
Mast Cell Degranulation ◽  
Signaling Proteins ◽  
Ros Production ◽  
Tnf Α ◽  
Listeria Monocytogenes Infection ◽  
Activation Pathways

Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1β, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.

scholarly journals Differential Involvement of Toll-Like Receptors 2 and 4 in the Host Response to Acute Respiratory Infections with Wild-Type and Mutant Haemophilus influenzae Strains

2005 ◽  
Vol 73 (4) ◽  
pp. 2075-2082 ◽  
Author(s):  
Eva Lorenz ◽  
Diana C. Chemotti ◽  
Alice L. Jiang ◽  
Letitia D. McDougal
Keyword(s):  
Haemophilus Influenzae ◽  
Host Response ◽  
Respiratory Infections ◽  
Acute Respiratory Infections ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Tlr2 Expression ◽  
Neutrophil Influx ◽  
Tnf Α

ABSTRACT We used a mouse model of acute respiratory infections to investigate the role of Toll-like receptor 2 (TLR2) and TLR4 in the host response to Haemophilus influenzae. Acute aerosol exposures to wild-type strains of H. influenzae showed that TLR4 function was essential for TNF-α induction, neutrophil influx, and bacterial clearance. To determine how lipooligosaccharide (LOS) modifications would affect the role of TLR4 in inducing the host response, we used acute infections with an H. influenzae strain expressing a mutation in the htrB gene. This mutant strain expresses an LOS subunit with decreased acylation. In response to H. influenzae htrB infection, tumor necrosis factor alpha (TNF-α) secretion remained TLR4 dependent. But the decrease in LOS acylation made the neutrophil influx and the bacterial clearance also dependent on TLR2, as shown by the decreased host response elicited in TLR2 knockout mice compared to C57BL/6 mice. A subsequent analysis of TLR2 and TLR4 gene expression by quantitative PCR indicated that TLR4 function induces TLR2 expression and vice versa. These results indicate that some changes in the LOS subunit of H. influenzae can favor signaling through non-TLR4 receptors, such as TLR2. The results also indicate a close interaction between TLR4 and TLR2 that tightly regulates the expression of both receptors.

scholarly journals Role of Flagellin and the Two-Component CheA/CheY System of Listeria monocytogenes in Host Cell Invasion and Virulence

2004 ◽  
Vol 72 (6) ◽  
pp. 3237-3244 ◽  
Author(s):  
Lone Dons ◽  
Emma Eriksson ◽  
Yuxuan Jin ◽  
Martin E. Rottenberg ◽  
Krister Kristensson ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Wild Type Strain ◽  
Tumor Necrosis Factor Receptor ◽  
Soft Agar ◽  
Initial Contact ◽  
Wild Type ◽  
Chemotaxis Proteins ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT The flagellum protein flagellin of Listeria monocytogenes is encoded by the flaA gene. Immediately downstream of flaA, two genes, cheY and cheA, encoding products with homology to chemotaxis proteins of other bacteria, are located. In this study we constructed deletion mutants with mutations in flaA. cheY, and cheA to elucidate their role in the biology of infection with L. monocytogenes. The ΔcheY, ΔcheA, and double-mutant ΔcheYA mutants, but not ΔflaA mutant, were motile in liquid media. However, the ΔcheA mutant had impaired swarming and the ΔcheY and ΔcheYA mutants were unable to swarm on soft agar plates, suggesting that cheY and cheA genes encode proteins involved in chemotaxis. The ΔflaA, ΔcheY, ΔcheA, and ΔcheYA mutants (grown at 24°C) showed reduced association with and invasion of Caco-2 cells compared to the wild-type strain. However, spleens from intragastrically infected BALB/c and C57BL/6 mice showed larger and similar numbers of the ΔflaA and ΔcheYA mutants, respectively, compared to the wild-type controls. Such a discrepancy could be explained by the fact that tumor necrosis factor receptor p55 deficient mice showed dramatically exacerbated susceptibility to the wild-type but unchanged or only slightly increased levels of the ΔflaA or ΔcheYA mutant. In summary, we show that listerial flaA. cheY, and cheA gene products facilitate the initial contact with epithelial cells and contribute to effective invasion but that flaA could also be involved in the triggering of immune responses.

scholarly journals CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models

2015 ◽  
Vol 93 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Alonso G.P. Guedes ◽  
Deepak A. Deshpande ◽  
Mythili Dileepan ◽  
Timothy F. Walseth ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Map Kinases ◽  
Surface Protein ◽  
Airway Smooth Muscle Cells ◽  
Wild Type ◽  
Partial Restoration ◽  
Cd38 Expression ◽  
Tnf Α ◽  
Deficient Mice

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3′ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

scholarly journals Attenuated Yersiniaenterocolitica Mutant Strains Exhibit Differential Virulence in Cytokine-Deficient Mice: Implications for the Development of Novel Live Carrier Vaccines

2003 ◽  
Vol 71 (4) ◽  
pp. 1804-1812 ◽  
Author(s):  
María S. Di Genaro ◽  
Marc Waidmann ◽  
Uwe Kramer ◽  
Niclas Hitziger ◽  
Erwin Bohn ◽  
...  
Keyword(s):  
Mutant Strain ◽  
Virulence Factors ◽  
Defense Mechanisms ◽  
Tyrosine Phosphatase ◽  
Bacterial Load ◽  
Systemic Infection ◽  
Mutant Mice ◽  
Wild Type ◽  
Mutant Strains ◽  
Deficient Mice

ABSTRACT Yersinia enterocolitica mutant strains, including mutants deficient in the chaperone SycH resulting in a functional deficiency in tyrosine phosphatase (YopH), Mn-cofactored superoxide dismutase (SodA), iron-repressive protein 1 (IRP-1), and Yersinia adhesin A (YadA), were demonstrated to be highly attenuated in wild-type C57BL/6 mice. TNFRp55−/−, IL-12p40−/−, and IL-18−/− mutant mice, in which the Yersinia wild-type strain causes severe systemic infections, were used to investigate whether these Yersinia mutant strains would be attenuated in immunodeficient hosts. A plasmid-cured Yersinia mutant strain was unable to colonize any of the mutant mice tested. A SycH-deficient mutant strain colonized intestinal tissues of these mice but was attenuated for systemic infection in all of the mutant mice. Both YadA- and Irp-1-deficient Yersinia mutants were still attenuated in IL-12−/− and IL-18−/− mice but were pathogenic in TNFRp55−/− mice. By contrast, a Yersinia sodA mutant was highly pathogenic for TNFRp55−/− and IL-12p40−/− mice while interleukin-18 (IL-18) was dispensable. This finding demonstrates that certain virulence factors enable yersiniae to compete with distinct cytokine-dependent host defense mechanisms. Moreover, while gamma interferon mRNA expression did not reflect protective host responses in cytokine-deficient mice, IL-10 expression coincided with a heavy splenic bacterial load and was associated with progressive infection courses. We can thus segregate minor (SodA), intermediate (YadA and IRP-1), and major (YopH) virulence factors of Y. enterocolitica. Finally, we demonstrate that, even in immunocompromised hosts, Yersinia sycH and, with some restrictions, irp-1 mutants may be suitable for use as live carrier vaccines.

scholarly journals H2-M3–restricted CD8+ T cells are not required for MHC class Ib–restricted immunity against Listeria monocytogenes

2006 ◽  
Vol 203 (2) ◽  
pp. 383-391 ◽  
Author(s):  
Sarah E.F. D'Orazio ◽  
Christine A. Shaw ◽  
Michael N. Starnbach
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Cd8 T Cells ◽  
T Cell Response ◽  
Mhc Class Ib ◽  
Wild Type ◽  
Histocompatibility Complex ◽  
Mutant Strains ◽  
Antigen Presenting ◽  
Deficient Mice

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8+ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8+ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T cells. We showed that immunization of MHC-Ia–deficient mice with fmt mutant Listeria resulted in stimulation of a protective memory response that cleared subsequent challenge with wild-type L. monocytogenes, despite the fact that M3-restricted CD8+ T cells did not proliferate in these mice. These data suggest that M3-restricted T cells are not required for protection against L. monocytogenes and underscore the importance of searching for new antigen-presenting molecules among the large MHC-Ib family of proteins.

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